title: Reciprocal changes in vanilloid (TRPV1) and endocannabinoid (CB1) receptors contribute to visceral hyperalgesia in the water avoidance stressed rat.
abstract: BACKGROUND
  Increasing evidence suggests that chronic stress plays an important role in the pathophysiology of several functional gastrointestinal disorders. We investigated whether cannabinoid receptor 1 (CB1) and vanilloid receptor 1 (TRPV1; transient receptor potential vanilloid 1) are involved in stress-induced visceral hyperalgesia.
  
  
  METHODS
  Male rats were exposed to 1 h water avoidance (WA) stress daily for 10 consecutive days. The visceromotor response (VMR) to colorectal distension (CRD) was measured. Immunofluorescence and western blot analysis were used to assess the expression of CB1 and TRPV1 receptors in dorsal root ganglion (DRG) neurons.
  
  
  RESULTS
  WA stressed rats demonstrated a significant increase in the serum corticosterone levels and faecal pellet output compared to controls supporting stimulation of the hypothalamic-pituitary-adrenal (HPA) axis. The VMR increased significantly at pressures of 40 and 60 mm Hg in WA stress rats compared with controls, respectively, and was associated with hyperalgesia. The endogenous CB1 agonist anandamide was increased significantly in DRGs from stressed rats. Immunofluorescence and western blot analysis showed a significant decrease in CB1 and a reciprocal increase in TRPV1 expression and phosphorylation in DRG neurons from stressed rats. These reciprocal changes in CB1 and TRPV1 were reproduced by treatment of control DRGs with anandamide in vitro. In contrast, treatment of control DRGs in vitro with the CB1 receptor agonist WIN 55,212-2 decreased the levels of TRPV1 and TRPV1 phosphorylation. Treatment of WA stress rats in situ with WIN 55,212-2 or the TRPV1 antagonist capsazepine prevented the development of visceral hyperalgesia and blocked the upregulation of TRPV1.
  
  
  CONCLUSIONS
  These results suggest that the endocannabinoid (CB1) and TRP (TRPV1) pathways may play a potentially important role in stress-induced visceral hyperalgesia.
authors.affiliation: Department of Internal Medicine, University of Michigan, Ann Arbor, MI 48109, USA. hongss@med.umich.edu
authors.forename: S
authors.initials: S
authors.lastname: Hong
authors.forename: J
authors.initials: J
authors.lastname: Fan
authors.forename: E S
authors.initials: ES
authors.lastname: Kemmerer
authors.forename: S
authors.initials: S
authors.lastname: Evans
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J W
authors.initials: JW
authors.lastname: Wiley
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000494:pharmacology; D048588:Benzoxazines / Q000494:pharmacology; D063385:Cannabinoid Receptor Modulators / Q000494:pharmacology; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D003345:Corticosterone / Q000097:blood; D003672:Defecation; D004576:Electromyography; D063388:Endocannabinoids; D005727:Ganglia, Spinal / Q000737:chemistry / Q000378:metabolism; D006930:Hyperalgesia / Q000378:metabolism* / Q000523:psychology; D007150:Immunohistochemistry; D007413:Intestinal Mucosa / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D023421:Models, Animal; D009025:Morpholines / Q000494:pharmacology; D009281:Naphthalenes / Q000494:pharmacology; D017288:Pain Threshold; D053284:Polyunsaturated Alkamides / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013057:Spectrum Analysis; D013315:Stress, Psychological / Q000378:metabolism*; D050916:TRPV Cation Channels / Q000032:analysis / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D048588:Benzoxazines; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D009025:Morpholines; D009281:Naphthalenes; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; C071423:capsazepine; D002211:Capsaicin; C078814:anandamide; D003345:Corticosterone